AHA: Post-ACS Drug Flops, Follow-Up Absent

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Varespladib methyl is a nonspecific pan-secretory phospholipase A2 inhibitor with favorable effects on LDL-C and CRP in patients with coronary disease. This study was designed to determine its effects on cardiovascular outcomes.

In patients with recent acute coronary syndrome, varespladib did not reduce the risk of recurrent cardiovascular events, but did significantly increase the risk of myocardial infarction (MI).

DALLAS -- A trial of the novel anti-inflammatory lipid-lowering agent varespladib that was halted for harm raised major ethical concerns when the sponsor failed to follow most of the patients afterward.

That risk was driven by a 66% relative increase in MI (rate 3.4% versus 2.2% with placebo, P=0.005), Stephen J. Nicholls, MBBS, PhD, of the South Australian Health and Medical Research Institute in Adelaide, and colleagues found.

However, after terminating the trial, the sponsor, Anthera Pharmaceuticals of Hayward, Calif., failed to follow more than two-thirds of the patients for 6-month survival, as specified in the protocol, and refused to release the data to the researchers, Nicholls pointed out at a press conference.

It wasn't until the drug license expired and the compound was returned to Eli Lilly and Shionogi more than a year later that those companies provided access.

Calls to Anthera were not answered. The company has other ongoing phase III trials, but the sole U.S. member of its scientific advisory board, Kenneth C. Kalunian, MD, of the University of California San Diego, said he was unaware of what happened with VISTA-16 and couldn't comment.

"There is an obligation when does an experiment on human beings to report the results of the experiment," said Robert Harrington, MD, of Stanford University and president of the AHA. "To not provide the academic investigators the data to do so is just completely unacceptable. People should be called to task for that."

But despite "monster documents" spelling out contracts between industry sponsors and universities, "that does happen," he told MedPage Today.

He cited a case where the industry sponsor of a dialysis device trial filed an ultimately unsuccessful injunction in federal court out of state to keep his group from publishing negative results.

There were other problems, too.

Inhibition of sPLA2 was a good target, but the study may have been underpowered and it's not clear whether the intervention was strong or specific enough, noted study discussant Philippe Gabriel Steg, MD, of Hôpital Bichat in Paris and Imperial College London.

Varespladib is a nonspecific inhibitor of sPLA2, which is a whole family of enzymes that generate phospholipid products implicated in atherosclerosis.

"The findings call into question whether sPLA2 is a valid target of therapy in atherosclerosis," Nicholls agreed at the press conference.

Another anti-inflammatory trial, this one targeting lipoprotein-associated phospholipase A2 (Lp-PLA2) with darapladib, also has been announced as failed, although not with the same signal of harm.

Steg cautioned that the results didn't rule out the inflammation hypothesis, though.

The Vascular Inflammation Suppression to Treat Acute Coronary Syndrome for 16 Weeks (VISTA-16) trial included 5,145 patients on four continents.

They were randomized within 96 hours of presentation with acute coronary syndrome to double-blind treatment with varespladib (500 mg) or placebo daily for 16 weeks atop atorvastatin (Lipitor) and other established therapies.

The trial was halted March 9, 2012 after an interim analysis showing a 6.1% rate of the primary composite with placebo (hazard ratio 1.25, 95% CI 0.97-1.61).

There was also a 36% excess in the composite secondary endpoint of cardiovascular mortality, MI, and stroke with varespladib (4.6% versus 3.8%, P=0.04).

The researchers pointed out that they couldn't exclude an excess mortality rate due to the increased rate of MI with varespladib.

"Favorable effects of varespladib on LDL cholesterol and CRP [C-reactive protein] were again demonstrated in the present trial, suggesting that other unfavorable consequences of sPLA2 inhibition or other unmeasured effects of varespladib influenced the clinical outcomes of treatment," Nicholls's group wrote in the paper.

"Possible explanations for the unfavorable outcomes include potentially inadequate penetration of varespladib into vascular cells to inhibit pro-inflammatory intracellular mediators."

Also, since recurrent MI soon after an acute coronary syndrome often reflects ongoing episodes of plaque rupture and thrombosis, the elevated rate of that outcome "might also suggest that the drug may have induced a prothrombotic state," they added.

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